Rationale: By 2014, 22 states had an obesity rate ?30% and none <20%. Costs due to obesity are estimated at $190B/yr. 72% of Veterans are overweight (45%) or obese (27%), of which 66% have hypertension and 31% have diabetes, the two most common comorbidities associated with obesity. Researchers use vagal nerve stimulation (VNS) to treat a number of conditions, including obesity. The vagal nerve is the parasympathetic branch of stomach innervation whereas the lesser-studied splanchnic nerve provides sympathetic innervation. Splanchnic nerve stimulation (SpNS) has also been used to treat obesity. Sensory afferents in these nerves relay information about the state of the stomach. How and why VNS and SpNS work remain unknown. Stimulus parameters vary widely and are often accompanied by side-effects. The limited success and undesired side effects are hypothesized to be due to the stimulus waveform. This grant seeks to understand the neural population code associated with stomach distension. It also assesses the effect of novel VNS and SpNS waveforms designed to mimic the neural population code and reduce side-effects on body weight in obese rats. Objective: The objectives of this study are to 1) elucidate the neural mechanisms underlying obesity and 2) develop and assess the effects of novel stimuli on eating behavior in obese rats. Numerous hypotheses will be tested through a series of animal experiments over a 4 year time period. Research Plan and Methodology: During Aim 1, in a series of non-survival experiments, the vagal and splanchnic nerves will be implanted with electrodes in rats. The rats will be healthy or made overweight or obese using a moderate or high-fat diet. The animal?s stomach will be distended with an intragastric balloon to mimic food consumption. Intragastric pressure will be recorded. Nerve recordings will provide insight to the neural response in the two nerves to stomach filling. The effect of diet and body mass index (BMI) on discharge pattern will be assessed. During Aim 2, in a series of survival experiments, nerve cuff electrodes will be implanted around the vagal and splanchnic nerves of rats. The rats will be either a healthy weight or obese. After healing, the rats will receive VNS, SpNS, or both using either standard time-invariant or novel time-variant waveforms. A time-variant waveform will be developed from recorded neural patterns and histology obtained in Aim 1 using 3D finite element models. Effects of stimulus location and waveform type on weight and activity will be determined over a 20-week period. Histology will be conducted to assess the effects of stimulus on nerve health. Immediate and Long-Term Career Goals: The immediate career goal is to become immersed within the field of obesity research and expand scientific understanding of how electrical stimulation applied to autonomic nerves can be used to reduce body weight. The long-term career goal is to become an independent clinical researcher with a lab at the LSCDVAMC that focuses on understanding and controlling the neural mechanism associated with obesity. Additional goals include 1) continuing to contribute to the local and national VA research community in the field of neural engineering and 2) advancing the body of scientific knowledge of how to interface with and control neurons in a manner that leads to natural outcomes. Future research will make extensive use of computer simulations, animal experiments, and human trials. Patterned nerve stimulation will be an expertise. Candidate Training: This CDA2 provides protected time to develop the following new skills: acute and chronic animal studies; animal surgeries; intraneural and extraneural nerve recording, processing, and analysis; electrode implantation; autonomic neuromodulation; clinical and surgical treatments of obesity;